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Gastro-Hepatology

Presentation: Patient with suspected Lynch syndrome

Lynch syndrome is the most common inherited cause of colorectal cancer, causing about 1 in 30 cases. By identifying patients with Lynch syndrome, we can offer preventive strategies to reduce bowel cancer risk and other cancers, and improve patient outcomes.

Example clinical scenario

A 35-year-old woman presents with anaemia and a positive faecal immunochemical test (FIT). Colorectal cancer was diagnosed following a colonoscopy and she underwent a right hemicolectomy. The tumour was found to be MSH2/MSH6-deficient, and constitutional (germline) genomic testing confirms a diagnosis of Lynch syndrome with a pathogenic variant in the MSH2 gene. The patient also reports a paternal family history of cancer.

When to consider genomic testing

  • Patients with mismatch repair deficient (dMMR) tumours with additional somatic (tumour) genomic testing that suggests Lynch syndrome should undergo constitutional (germline) genomic testing.
    • All new diagnoses of colorectal and endometrial cancer should have tumour testing to identify whether it is a dMMR tumour, which indicates a possible diagnosis of Lynch syndrome. In colorectal cancer either immunohistochemistry for mismatch repair proteins or microsatellite instability testing may be used as the index test, and some patients may require BRAF or MLH1 promoter methylation testing before germline testing with the R210 constitutional panel (see NICE guidance DG27).
  • Patients under 40 years old with colorectal cancer should undergo R211 constitutional panel testing irrespective of the MMR status. This panel includes Lynch syndrome and polyposis syndrome genes.
  • The National Genomic Testing Directory eligibility criteria for constitutional (germline) genomic testing with the R210 constitutional panel are:
    • Clinical criteria for constitutional (germline) testing in an affected individual: The proband has a dMMR tumour where results of additional testing suggest Lynch syndrome. This may include BRAF testing in MLH1-deficient colorectal cancers and MLH1 hypermethylation testing in BRAF-negative colorectal cancers and all MLH1-deficient uterine cancers.
    • Testing of other people at risk of a diagnosis of Lynch syndrome: Testing of other individuals, including those with a family history of cancer, or of deceased individuals may be considered as outlined in the test directory (R210).
  • Cascade (predictive) testing should be offered to first-degree relatives of a patient with a confirmed genetic diagnosis of Lynch syndrome via referral to clinical genetics (R242). However, testing of people other than those with dMMR cancers should only be performed by clinical genetics or highly specialised services.
  • Constitutional (germline) genomic testing may occasionally be appropriate outside these criteria. If you have a strong clinical suspicion of Lynch syndrome, discuss with your local Genomic Laboratory Hub.

What do you need to do?

  • Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
  • Where constitutional (germline) genomic testing is required to confirm Lynch syndrome with dMMR colorectal cancer, the appropriate panel to choose is:
    • R210 Inherited MMR deficiency (Lynch syndrome): This involves testing a small panel of genes or loci specific for Lynch syndrome, such as MLH1, MSH2, MSH6, PMS2 and EPCAM.
  • Where there is no constitutional (germline) pathogenic variant in MMR genes in a patient with dMMR tumours without MLH-1 hypermethylation or BRAF pathogenic variant, they should undergo somatic (tumour) testing with a colorectal cancer gene panel.
  • R211 Inherited polyposis and early onset colorectal cancer: May be considered for any colorectal cancer diagnosis under 40 years of age, and includes the genes on the R210 panel, but also polyposis syndrome genes (see Presentation: Patient with polyposis).
  • If you diagnose a cancer patient with Lynch syndrome, they should immediately be referred to clinical genetics for ongoing holistic management, including (in England) colonoscopic surveillance through the Lynch syndrome bowel cancer screening programme. You should:
    • obtain a complete family history of cancers and establish a genetic pedigree;
    • offer cascade (predictive) testing to first-degree relatives of a patient with a confirmed genetic diagnosis of Lynch syndrome (this testing is performed by clinical genetics services); and
    • refer first-degree relatives of affected individuals to the clinical genetics service for genetic counselling prior to testing.
  • For detailed gene-specific management for patients with Lynch syndrome, please refer to the relevant Cancer Genetics Group leaflets and the guidelines by Monahan and others.
  • If in doubt, consult your local clinical genetics service.
  • Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 28/02/2025
  • Next review due: 28/02/2026
  • Authors: Dr Stephanie Poo
  • Reviewers: Dr Kevin Monahan

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